Những khám phá và phát triển của hoá dược

Đây là bài giảng cho các lớp cao học ngành kỹ thuật hoá học về các khám phá và phát triển trong lĩnh vực hoá dược, tài liệu được trình bày bằng tiếng anh, rất hữu ích cho các bạn vì có nhiều hình ảnh minh hoạ các khám phá trong lịch sử hoá dược.

‰ G L Patrick, An introduction to medicinal chemistry, Oxford university

‰ Bill Bennett, Graham Cole, Pharmaceutical production – An engineering

guide, Chemical Engineers (IChemE) 2003.

‰ Michael Levin, Pharmaceutical Process Scale-up, Marcel Dekker, Inc

2002

‰ David G Watson, Pharmaceutical Analysis, Harcourt Publishers 1999.

‰ Gary Walsh, Brendan Murphy, Biopharmaceuticals - An industrial

perspective, Kluwer Academic Publishers 1999 (C) HKD 2013

HISTORY IN BRIEF

‰ Primitive traces of medicinal chemistry:

9 Clay tablets (2600 BC, Sumérie): 1000 plants

9 Ebers Papyrus (1500 BC, Egypt): 800 preparations

9 Hippocrates (440-377 BC)

‰ … until 19th century: preponderance of plant-based potion.

9 Empiricism and theory of signature: similarity in characteristics of plantsand the organ

Ex: Color Red / Bood () haemostatic derived from hibiscus)

Shape / Organ (crocus bulb for gout treatment, big toe)

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‰ 1763: medicinal properties of extract of willow bark and leaves observed

Edward Stone (headache, stomachache, and other body pain)

‰ 1829: Isolation of salicin by H Leroux

‰ 1853: Transformation from salicin to acetyl salicylic acid by CharlesGerhardt

‰ 1899: Bayer’s market launch of Aspirine.

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HISTORY IN BRIEF

‰ From 19 th century: DRUG = PURE COMPOUND.

9 1803: Isolation of morphine from opium poppy by Friedrich Serturner.

9 1819-1820: Isolation of strychnine, caffeine, quinine and colchicine by

Pelletier and Caventou

‰ End of 19 th century – Beginning of 20 th century:

9 “Lock - Key” (E Fisher)

9 “Magic Bullet” (P Ehrlich): structure – activity

‰ Screening and selection of lead(isolation, structure, patent).

‰ Elimination of molecules being difficult to project (complex structure,

‰ Optimization of pharmacodynamic properties.

‰ Optimization of pharmacokinetic properties and solubility.

The best molecule (less toxic, in-vivo active, formulable)

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OPTIMIZATION PHASE

M McCoss, Organic chemistry in drug discovery, T A Baillie Science 2004, 303, 1810(C) HKD 2013

DRUG DISCOVERY AND DEVELOPMENT

PRECLINICAL PHASE (animal test)

‰ Exact knowledge of the molecule (pilot scale synthesis with purity > 99%,

clearly identified impurities, stability within 6 month, available galenic form)

‰ Toxicity (acute, chronic, sub-chronic (5-90 days)).

‰ Evaluation of mutagenic risk.

‰ Studying of effects on reproduction (fertility, embryo, death and postnatality).

CLINICAL PHASE I

‰ The first administration to human (~ 1 year with > 100-200 volunteers → 5-30

kg)

‰ Studying clinical and biological tolerance on human.

‰ Determination of maximum tolerated dose (1st administrated dose = 1/10maximum dose without unacceptable toxicity on animal)

‰ Verification of pharmacokinetic properties

CLINICAL PHASE IIa: verification of therapeutic effects and side effects in shortterm

End of development research: molecule = medication ?

Beginning of industrial development: molecule  medication.

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DRUG DISCOVERY AND DEVELOPMENT

CLINICAL PHASE IIb

‰ Determination of effective therapeutic dose, dosage and type of

administration (~ 2 years on 20-80 volunteers → 30-100 kg).

‰ Double blind test / placebo or existing medications (cancer or AIDS).

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CLINICAL PHASE III (~ 3 years, 50-300 kg)

‰ Demonstration of surety and effectiveness of novel medication (larger

‰ Favorable ratio of Benefits – Risks.

‰ Impeccable pharmaceutical quality.

‰ Safety methods in preclinical and clinical trials.

‰ Clinical effectiveness proved in claimed indication.

PHARMACOVIGILANCE (CLINICAL PHASE IV)

‰ Drug: at molecular scale, drug means a substance being able to interact with a biological system in order to give a biological response.

‰ Official definition of Drug: a drug is a chemical substance which may have medicinal, intoxicating, performance enhancing or other effects when taken or put into a human body

or the body of another animal and is used in the treatment, cure, prevention, or diagnosis

of disease or used to otherwise enhance physical or mental well-being.

‰ Drug = active ingredient + excipient.

‰ Excipient:

9 Carrier for active ingredients.

9 Stabilize the active ingredient.

9 Antiadherents (magnesium stearate), Binders(saccharide, protein, polymer).

9 Disintegrants.

9 Fillers (lactose, sucrose, glucose, mannitol, sorbitol).

9 Flavours, Colors , Preservatives , Sweeteners. (C) HKD 2013

DRUG DISCOVERY

Source of Drugs

→ 52% drugs from nature or nature-inspired.

Atorvastatine (Lipitor): best-seller drugs – 11 billions USD in 2004

Natural molecules

M S Butler, Nat Prod Rep 2005, 22, 1620.

Frogs Fishes Snakes

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DRUG DISCOVERY

Natural molecules

M S Butler, Nat Prod Rep 2005, 22, 1620.

Plants (300.000 – 400.000 species, 10% investigated)

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Natural molecules

M S Butler, Nat Prod Rep 2005, 22, 1620.

Bacteria, fungus (> 1.000.000 species, but <10% bacteria , 5% fungus investigated)

Marine sources: algae, corals, sponges (500 000 species, less-investigated)

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DRUG DISCOVERY

Nature-inspired molecules

‰ Inspiration from receptor’s natural ligand

‰ Inspiration from enzyme’s natural substrate

Nature-inspired molecules

O O

OH N

R R=H adrenalineR=Me noradrenaline

Increased size (selectivity and duration)

Catechol bioisostere (toxicity)

Increased size (selectivity and duration)

N

O

H

OH N O

OH N O

‰ Inspiration from (“mee too” drugs)

9 Economic and competitive aspects

9 Lower risk: guaranteed activity and validated biologic tests

9 Improvement of pharmacological profile: activity, selectivity, toxicity …

‰ Test of intermediate molecules of the synthesis route: structure relating to target

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Synthetic molecules

N O

O

N N

O O

Cialis(Tadalafil)

Eli Lilly

N

NNN O

O

S N

O O N

Levitra(Vardenafil)Bayer

Issues: short durationMultiple side effects and incompatibility with other drugs

N N N N O

O

S N

O O N

ViagraPfizer

Fewer side effects and

incompatibility with other drugs

36h duration (“the weekend pill”)

New Lead Optimisation Projects (LO)

Candidate Drug (CD)

Active-to-Hit (AtH)

High-throughput screening (HTS)

• validated, tractable targets

• target selection for HTS

• industrialised process

• HTS assay technologies and automation

• chemical diversity

• sample selection for HTS

How?

“An industrialised process which brings together validated,

tractable targets and chemical diversity to rapidly identify

novel lead compounds for early phase drug discovery”

50-70% of new drug projects originate from a HTS

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DRUG DISCOVERY

High-throughput screening (HTS)

OH N Cl O O

chemicalspace

compoundcollection

compoundselection

human & pathogen

genomes

validated/

tractabletargetstarget

ID

HT ScreenDevelopment

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DRUG DISCOVERY

Fragment-based lead discovery

‰ Combination of two fragment resulting activity

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Fragment-based lead discovery

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DRUG DISCOVERY

Fragment-based lead discovery

Structure – Activity relationship

9 Identifying the functional group giving activity

9 Method: transforming, removing or masking each group

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‰ Role of carbonyl group

Structure – Activity relationship

‰ Isostere: to alter the character of the molecule in as subtle a way as possible.

Structure – Activity relationship

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LEAD OPTIMIZATION

Pharmacodynamics

‰ Identification of pharmacophore

9 Functional groups for target interaction

9 Relative position of each functional groups

9 Acvitve conformations

‰ Simplification of lead molecule

9 Discard non-essential parts of the structure without losing activity (typically inthe case of natural compounds)

Excessive simplicity:

lost of activity / selectivity due to lower restriction of rotation

9 Elimination of asymmetric centers

Pharmacodynamics

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LEAD OPTIMIZATION

‰ Rigidification of lead molecule: to 'lock' the drug molecule into a more rigid

conformation such that it cannot take up these other shapes or conformations(hence other receptor interactions and side-effects are eliminated)

Pharmacodynamics

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‰ Rigidification of lead molecule

Pharmacodynamics

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LEAD OPTIMIZATION

‰ Drug design for pharmacodynamic problems

9 Extension of the structure

9 Ring extensions/contractions

9 Chain extensions/contractions

Pharmacodynamics

‰ Drug design for pharmacodynamic problems

‰ Electronic effects (effect on a drug's ionization or polarity ) how easily a drug

can pass through cell membranes or how strongly it can bind to a receptor)

‰ Hydrophobicity (how easily it crosses cell membranes and may also be

important in receptor interactions)

9 Constant of Hansch

Quantitative structure - activity relationships

(QSAR)

Quantitative structure - activity relationships

y Parent drugs -> metabolites

y Lipid soluble -> water soluble

(hard to excrete) -> easier

y Water soluble -> lipid soluble

y More toxic metabolite

y Inactive prodrug -> active drug

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LEAD OPTIMIZATION

‰ Metabolism (xenobiotic metabolism)

9 Phase 1: Oxydation, reduction, hydrolysis (→introducing reactive or polar

groups into xenobiotics)

Oxidation carried out in liver by Cytochromes P450

Pharmacokinetics

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‰ Metabolism

9 Phase 1: Oxidation, reduction and hydrolysis.

Reduction (NADPH-cytochrome P450 reductase) and hydrolysis

Pharmacokinetics

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LEAD OPTIMIZATION

‰ Metabolism

9 Phase 2: Conjugated reactions (the activated xenobiotic metabolites are

conjugated with charged species such as glutathione (GSH), sulfate, glycine,

or glucuronic acid

) Products of conjugation reactions have increased molecular weight and tend to

beless active than their substrates (unlike Phase I reactions which often produceactive metabolites)

) The addition of large anionic groups (such as GSH) detoxifies reactiveelectrophiles and produces more polar metabolites that cannot diffuse across membranes, and may, therefore, be actively transported

9 Phase 3: further modification and excretion.

Pharmacokinetics

‰ Objectives

9 Optimization of hydrophile – hydrophobe equilibrium: solubility in blood,

permeability through cell membrane → lowering fast excretion

9 Optimization of chemical, metabolic stability: gastric acidity, digestive

enzymes, metabolic enzymes

9 Balancing PD and PK.

in vitro antibiotic agent

but less active in vivo

(due to the present of more polar groups) → Alkylation of the groups

→ decreasing the activity

Pharmacokinetics

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LEAD OPTIMIZATION

Lipinski's rule of five (Pfizer’s rule, 1997)

9 A rule of thumb to evaluate druglikeness or determine if a chemical compoundwith a certain pharmacological or biological activity has properties that wouldmake it a likely orally active drug in humans

9 Describes molecular properties important for a drug's pharmacokinetics in thehuman body, including their ADME properties However, the rule does not predict if a compound is pharmacologically active.

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Drug-like molecules

9 Druglikeness is a qualitative concept used in drug design for how "druglike" asubstance is with respect to factors like bioavailability It is estimated from themolecular structure before the substance is even synthesized and tested Adruglike molecule has properties such as:

ƒ Solubility in both water and fat, as an orally administered drug needs to passthrough the intestinal lining after it is consumed, carried in aqueous blood andpenetrate the lipid cellular membrane to reach the inside of a cell (log P)

ƒ Potency at the target of interest High potency (high value of pIC50) is adesirable attribute in drug candidates, as it reduces the risk of non-specific,off-target pharmacology at a given concentration When associated with lowclearance, high potency also allows for low total dose, which lowers the risk

of idiosyncratic drug reactions

9 Substructures that have known chemical or pharmacological properties Forexample, alkylnitro compounds tend to be irritants, and Michael acceptors,such as enones, are alkylating agents and thus potentially mutagenic andcarcinogenic

Lipinski's rule of five (Pfizer’s rule, 1997)

9 In general, an orally active drug (orally bioavailable drug) has no more than one

violation of the following criteria:

ƒ Not more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one

or more hydrogen atoms)

ƒ Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms)

ƒ A molecular mass less than 500 daltons

ƒ An octanol-water partition coefficient log P not greater than 5

ƒ Extension: In particular, compounds which meet only the two criteria of:

9 10 or fewer rotatable bonds and

9 polar surface area equal to or less than 140 Å2.

are predicted to have good oral bioavailability

)There are many exceptions to Lipinski's Rule (C) HKD 2013

LEAD OPTIMIZATION

Pharmacokinetics

‰ Absorption

9 Variation of chains: hydrophobicity= f (length of the chain)

9 Variation of polar or non-polar groups: increase / decreasehydrophobicity

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‰ Pro-drug

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